Genes on rat chromosome 3 are involved in the development of obesity and sex-specific dyslipidemia: Lesson from congenic DA.WOKW rats

Aim: WOKW rats develop a number of facets of the metabolic syndrome which is polygenetically inherited as shown by mapping of quantitative trait loci (QTLs) for single facets on different chromosomes in a cross of WOKW and disease-resistant DA rats. Beside others, a QTL for total cholesterol was mapped on chromosome 3. To confirm this QTL, chromosome 3 congenic DA.WOKW rats (DA.3W) were generated, genetically and phenotypically characterised.

Methods: DA.3W rats were generated as speed-congenics by a cross of WOKW and DA rats using marker-aided selection. The resulting cross hybrids were repeatedly backcrossed with DA using animals which were heterozygous at loci D3Mgh3, D3Mit3, D3Mgh5 and were most homozygous for DA alleles at 180 background loci. After 5 backcross generations, the animals were intercrossed. Animals homozygous for WOKW alleles at the loci on chromosome 3 were selected and founded the congenic DA.3W rat strain.

Founder animals were fine mapped with 37 polymorphic markers on chromosome 3. 15 males and 15 females of DA.3W, DA and WOKW were longitudinally characterised for body weight, blood glucose, serum lipids, leptin and insulin from the 8th to 32nd weeks of life. Rats were killed at 32 weeks, left and right inquinal adipose pads were removed and weighed to determine the adiposity index (AI).

Results: The exchanged region on chromosome 3 amounts to 72.5 Mb and spans from position 97.5 to 170 Mb. The phenotypic data showed that the body weight of congenic DA.3W rats was significantly higher than that of DA rats but, was significantly lower than that of WOKW rats. The AI was also significantly higher in DA.3W than in DA but was lower than in WOKW. In addition, DA.3W rats were characterized by significantly higher leptin and insulin values than found in parental DA rats. Fasting and non-fasting serum total cholesterols were significantly higher in female DA.3W in comparison with female DA and WOKW rats. In contrast, serum total cholesterol was comparable in DA.3W, DA and WOKW males.

Conclusions: The results clearly show that WOKW genes on chromosome 3 increase body weight and AI in males and females whereas serum lipids are only increased in congenic DA.3W females. Therefore, WOKW genes on this chromosomal region are involved in the development of obesity with hyperinsulinemia and hyperleptinemia as well as of sex-specific dyslipidemia.